Efficient formal total synthesis of the erythrina alkaloid (+)-erysotramidine, using a domino process

Article abstract of DOI:10.1021/ol901980u

A domino process consisting of an amidation, spirocyclization, and formation of an iminium ion and electrophilic aromatic substitution of a phenylethylamine and a ketoester leads to the spirocyclic skeleton of (+)-erysotramidine, which can be further tran

Full text of DOI:10.1021/ol901980u

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5230-5233
Efficient Formal Total Synthesis of the
Erythrina Alkaloid (+)-Erysotramidine,
Using a Domino Process
Lutz F. Tietze,*,† Nina To¨lle,† Daniel Kratzert,‡ and Dietmar Stalke‡
Institute of Organic and Biomolecular Chemistry, Georg-August UniVersity Go¨ttingen,
Tammannstrasse 2, 37077 Go¨ttingen, Germany, and Institute of Inorganic Chemistry,
Georg-August UniVersity Go¨ttingen, Tammannstrasse 4, 37077 Go¨ttingen, Germany
ltietze@gwdg.de
Received September 18, 2009
ABSTRACT
A domino process consisting of an amidation, spirocyclization, and formation of an iminium ion and electrophilic aromatic substitution of a
phenylethylamine and a ketoester leads to the spirocyclic skeleton of (+)-erysotramidine, which can be further transformed into the natural
alkaloid.
The erythrina alkaloids, 2 and 3, containing the spirocyclic
skeleton 1 comprise a widespread class of natural products
which can be found in tropical and subtropical plants of
the erythrina genus (Figure 1). They show a wide range
of pharmacological effects, including sedative, hypoten-
sive, anticonvulsive, CNS depressing, and curare-like
properties.1 Due to their biological activities and their
interesting spirocyclic structure, several total syntheses
of selected compounds of this family of natural products
have been performed.2 However, despite the great number
of publications only a few syntheses lead to the enan-
tiopure alkaloids.2 Examples are the total synthesis of (+)-
ꢀ-erythroidine (2) by Hatakeyama et al. in 2006 in 24
linear steps using a 2-fold ring-closing metathesis reaction3
† Institute of Organic and Biomolecular Chemistry.
(2) (a) Gao, S.; Tu, Y. Q.; Hu, X.; Wang, S.; Hua, R.; Jiang, Y.; Zhao,
Y.; Fan, X.; Zhang, S. Org. Lett. 2006, 8, 2373–2376. (b) Kim, G.; Kim,
J. H.; Lee, K. Y. J. Org. Chem. 2005, 71, 2158–2187. (c) Padwa, A.; Hennig,
R.; Kappe, C. O.; Reger, T. S. J. Org. Chem. 1998, 63, 1144–1155. (d)
Padwa, A.; Kappe, C. O.; Reger, T. S. J. Org. Chem. 1996, 61, 4888–
4889. (e) Tsuda, Y.; Hosoi, S.; Nakai, A.; Sakai, Y.; Abe, T.; Ishi, Y.;
Kiuchi, Y.; Sano, T. Chem. Pharm Bull. 1991, 39 (6), 1365–1373. (f)
Tanaka, H.; Tamura, Y.; Shibata, M.; Ito, K. Chem. Pharm. Bull. 1986,
34, 24.
‡ Institute of Inorganic Chemistry.
(1) (a) Boekelheide, V. In The Alkaloids; Manske, R. H. F., Ed.;
Academic Press: New York, 1960; Vol. 7, pp 201-227. (b) Hill, R. K. In
The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967;
Vol. 9, pp 483-515. (c) Dyke, S. F.; Quessy, S. N. In The Alkaloids;
Rodrigo, R. G. A., Ed.; Academic Press: New York, 1981; Vol. 18, pp
1-98. (d) Jackson, A. H. In Chemistry and Biology of Isoquinoline
Alkaloids; Phillipson, J. D., Margaret, M. F., Zenk, M. H., Eds.; Springer:
Berlin, Germany, 1985; pp 62-78. (e) Chawala, A. S.; Jackson, A. H. Nat.
Prod. Rep. 1984, 1, 371–373.
(3) Fukumoto, H.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew.
Chem., Int. Ed. 2006, 45, 2731–2734.
10.1021/ol901980u CCC: $40.75
Published on Web 10/27/2009
 2009 American Chemical Society

the amine 7. Thus, according to our former investigations7
treatment of a mixture of 6 and 7 with AlMe3 in the presence
of a catalytic amount of a Lewis acid should lead to 5 in a
domino process consisting of an amidation, spirocyclization,
formation of an iminium ion, and electrophilic aromatic
substitution.
The necessary cyclohexanone derivative 6 was prepared
by a conjugate addition of the silyl zincate 8, developed by
Oestreich,8 to cyclohexenone in the presence of catalytic
amounts of CuI (Scheme 2).
Scheme 2. Synthesis of (S,S)-6 and (R,R)-6
Figure 1. Erythrina alkaloids.
and of (+)-erysotramidine (3) by Simpkins et al. in 13
linear steps employing a chiral imine as intermediate.4
It was our goal to develop a shorter access to these
alkaloids using a domino process.
Thus, the domino concept has proven to allow a highly
efficient access to a wide variety of compounds with the
advantage to meet the demand for an economically favorable
and ecologically benign chemistry.5,6
Herein we describe a short and efficient synthesis of the
alcohol 4, which can be converted into (+)-erysotramidine
(3) in four steps with a known procedure (Scheme 1).4
The in situ generated enolate was then quenched with
ethyl bromoacetate (9) to give the ketoester 6 in 96% yield
as a single diastereomer with a 2,3-trans-orientation. So
far we did not investigate an enantioselective conjugate
addition, since rac-7 could easily be resolved on a chiral
stationary phase to give (S,S)-6 and (R,R)-6 with g99%
ee. Reaction of the ketoester (S,S)-6 with the phenylethy-
lamine 7 with 2 equiv of AlMe3 in the presence of 15
mol % of indium triflate followed by treatment with
trifluoric acid led to a 4:1 mixture of the desired
spirocyclic compounds 5 and 10 in 92% yield (Scheme
3). The two diastereomers could easily be separated by
chromatography on silica gel. Since the absolute config-
uration of the enantiomeric cyclohexanone derivatives 6
was not known at the time of their usage, we also
performed the domino reaction with (R,R)-6 and compared
the optical rotation of the alcohols obtained from 5 and
its enantiomer with that of the known alcohol 4. Moreover,
the absolute confguration of 5 was determined by X-ray
crystallography (Figure 2; see the Supporting Information
for details).
Scheme 1
.
Retrosynthesis of (+)-Erysotramidine (3) via the
Alcohol 4
As a mechanism for the domino process we presume
that first an aluminum amide is formed by reaction of the
amine 7 with AlMe3, which then attacks the ester function
exclusively to form an azaenolate. This reacts with the
carbonyl moiety to give two isomeric enamines. Under
treatment with TfOH the iminium ion 11 is obtained,
which then undergoes an electrophilic aromatic substitu-
tion (Scheme 4).
The alcohol 4 can be traced back to the spirocyclic silane
5, which can be further disconnected to the keto ester 6 and
(4) Blake, A. J.; Gill, C.; Greenhalgh, D. A.; Simpkins, N. S.; Zhang,
F. Synthesis 2005, 19, 3287–3292.
Under the assumption that the presumed 2,3-trans-orienta-
tion at the cyclohexane moiety in the iminium ion 11 is
(5) (a) Tietze, L. F.; Haunert, F. In Stimulating Concepts in Chemistry;
Shibasaki, M., Stoddard, J. F., Vo¨gtle, F., Eds.; Wiley-VCH: Weinheim,
Germany, 2000; pp 39-64. (b) Tietze, L. F.; Modi, A. Med. Res. ReV.
2000, 20, 304–322. (c) Tietze, L. F. Chem. ReV. 1996, 115–136. (d) Tietze,
L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131–163.
(6) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006.
(7) (a) Tietze, L. F.; Bialy, S. A. A.; Braun, H. Angew. Chem., Int. Ed.
2004, 43, 5391–5393. (b) Tietze, L. F.; To¨lle, N.; Noll, C. Synlett 2008,
525–528.
(8) Oestreich, M.; Weiner, B. Synlett 2004, 2139–2142.
Org. Lett., Vol. 11, No. 22, 2009
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Scheme 3. Synthesis of 5 and 10, Using a Domino Process
retained in the products, the formation of two diastereomers
was expected.
assume that the reaction proceeds under kinetic control
since the difference of the ground state energies of 5 and
10 using a simplified model in the DFT calculations sums
up to 29 kJ/mol, which is not in accordance with the ratio
of 5 and 10 found in the experiment (for simplification,
the PhMe2Si group was replaced by a Me3Si group and
the two methoxy groups were replaced by a methylene-
dioxo group).
As the final step for the synthesis of the alcohol 4 a
Tamao-Fleming oxidation of the silane 5 was performed,
using tetrafluoroboronic acid etherate at 80 °C under
microwave irradiation, which is followed by oxidation of
the formed fluorosilane with H2O2 in the presence of KF/
KHCO3 (Scheme 5). The reaction sequence led to a 9:1
mixture of the desired alcohol 4 and its epimer 12 in 80%
yield, which could be separated by chromatography on
silica gel. Performing the oxidation at a higher temperature
such as 100 °C results in a slightly better yield of 83%,
however, with loss of the stereointegrity of the stereogenic
center at the silane moiety yielding 4 and 12 as a 1:1
mixture. Oxidation of the mixture of 4 and 12 with IBX
gave the ketone 13 as a single compound, proving indeed
12 as an epimer of 4 with the opposite configuration at
the carbon bearing the hydroxyl group (Scheme 5). We
also performed the Tamao-Fleming oxidation of 10 to
give two diastereomeric alcohols which have a different
relative configuration as found in 4 and 12, clearly
showing that rings A and B in 10 are not cis-annelated.
Since 4 is an intermediate in the synthesis of (+)-
erysothramidine (3) by Simpkins et al.4 its preparation
constitutes a formal synthesis of 3 with a highly reduced
number of steps.
Figure 2. Structure of 5 showing the absolute configuration.
An attack from above, anti to the acetyl moiety (re-
face), would lead to the cis-annelated compound 5, which
is the thermodynamically favored product (see also
theoretical investigations in the Supporting Information)
and the main product in the transformation (Scheme 4).
The attack from below would give the thermodynamically
disfavored trans-annelated compound 10. However, we
Scheme 4. Intramolecular Electrophilic Aromatic Substitution of Iminium Ion 11 from the Two Diastereotopic Faces
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Org. Lett., Vol. 11, No. 22, 2009

Scheme 5. Tamao-Fleming Oxidation of the Silane 5
In conclusion we have developed an effective synthesis of
erysotramidine that employs two highly efficient multistep pro-
cesses. With this modular approach applying different building
blocks, access to a variety of analogous structures is possible.
Supporting Information Available: Experimental pro-
cedures, spectral data, and crystallographic information files
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
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